Long chain fatty acids are essential components of glycolipids, phospholipids, and cholesterol, which are building blocks for biological membranes, and are essential constituents of triglycerides, which are biological fuel molecules. Long chain fatty acids are also substrates for eicosanoid production, and are important in the functional modification of certain complex carbohydrates and proteins.
Fatty acid synthesis, lipogenesis, is similar in prokaryotes and eukaryotes. In prokaryotes, seven enzymes catalyze the various synthetic steps. In the first step, acetyl-CoA carboxylase (ACC) synthesizes malonyl-CoA from acetyl-CoA and bicarbonate. Subsequently, malonyl transacylase attaches malonyl-CoA to the 4'-phosphopantetheine prosthetic group of acyl carrier protein (ACP), producing malonyl-ACP. ACPs serve as scaffolds which are responsible for holding the components of the growing fatty acid chain in close proximity to the appropriate enzyme. Acetyl-ACP is produced by the action of acetyl transacylase on acetyl-CoA and ACP. Acetyl-ACP and malonyl-ACP are condensed and reduced by the enzyme .beta.-ketoacyl-ACP synthase, forming D-3-hydroxybutyryl-ACP. D-3-hydroxybutyryl-ACP then undergoes further enzymatic reactions, including dehydration and a second reduction, to produce butyryl-ACP, the end product of the first round of elongation. Subsequent rounds of elongation proceed until a 16-carbon chain is produced. This 16-carbon chain is cleaved from ACP to produce palmitate. Further elongation, as well as unsaturation, of palmitate by accessory enzymes of the endoplasmic reticulum produces the variety of long chain fatty acids required by the individual cell (Siggaard-Andersen, M., et al. (1994) Proc Natl Acad Sci 91:11027-11031).
Eukaryotic lipogenesis involves the same biochemical reactions as prokaryotic lipogenesis. ACC again catalyzes the first step in this process, producing malonyl-CoA. However, the enzymes which catalyze the remaining reactions are covalently linked into a single polypeptide chain, referred to as the multifunctional enzyme fatty acid synthase (FAS). FAS catalyzes the synthesis of palmitate from acetyl-CoA and malonyl-CoA (Wakil, S. J., et al. (1989) Biochem 28:4523-4530).
Lipogenesis occurs at a low and fairly constant level in the cells of most mammalian tissues. In some tissues, such as mammalian sebaceous glands or avian uropygial glands, fatty acid synthesis is regulated by the cellular differentiation state. In liver, adipose tissue, and lactating mammary glands, diet, hormones, and the availability of circulating fuel molecules regulate the activities of ACC and FAS. Carbohydrate intake in excess of that required for immediate energy needs is stored as triacylglycerol. When carbohydrate intake is less than required for immediate energy needs, stored triacylglycerol is utilized as fuel. Changes in diet are communicated by changes in levels of circulating hormones and fuels. Insulin, thyroid hormone, and high-carbohydrate low-fat diets are activators of lipogenesis, and glucagon and elevated levels of circulating fuel molecules are negative effectors of lipogenesis. In addition, growth hormone, glucocorticoids, and some growth factors regulate the level of lipogenesis under certain conditions (Hillgartner, F. B., et al. (1995) Physiol Rev. 75:47-76).
The role of elevated cholesterol levels in hypertension, atherosclerosis, and coronary artery disease is well established. Fatty acid metabolism produces molecules, including cholesterol, that are associated with the genesis of these disease states. Fatty acids are also essential precursors for eicosanoid synthesis. Eicosanoids, including prostaglandins, prostacyclins, thromboxanes, and leukotrienes, are important mediators of inflammatory responses.
Immunohistochemical studies have associated elevated levels of FAS with high-grade advanced stage prostatic cancers and with poor prognosis in breast cancers (Shurbaji, M. S., et al. (1996) Hum Pathol 27:917-921). Cell lines derived from human ovarian, endometrial, breast, colorectal, and prostatic cancers show increased fatty acid synthesis and a preference for use of endogenously-synthesized fatty acids over dietary lipids as fuel for cellular function (Pizer, E. S., et al. (1996) Cancer Res 56:1189-1193). FAS is associated with a higher degree of tumor recurrence in patients with early-stage breast carcinoma (Alo' et al., (1996) Cancer 77:474-482).
In a rat model for non-insulin-dependent diabetes mellitus, increased hepatic FAS activity results in hypertriglyceridemia (Kazumi, T., et al. (1997), Endocr J 44:239-245). High-fat low-carbohydrate diets regulate the expression of FAS, and inhibit FAS activity. Loss of this regulation is associated with weight gain and the development of obesity (Hillgartner, supra).
The discovery of a new human fatty acid synthase-like protein and the polynucleotides encoding it satisfies a need in the art by providing new compositions which are useful in the diagnosis, prevention, and treatment of cancer and inflammation.